TY  - BOOK
AU  - Wakeling,Matthew N.
AU  - Owens,Nick D.L.
AU  - Hopkinson,Jessica R.
AU  - Johnson,Matthew B.
AU  - Houghton,Jayne A.L.
AU  - Dastamani,Antonia
AU  - Flaxman,Christine S.
AU  - Wyatt,Rebecca C.
AU  - Hewat,Thomas I.
AU  - Hopkins,Jasmin J.
AU  - Laver,Thomas W.
AU  - van Heugten,Rachel
AU  - Weedon,Michael N.
AU  - De Franco,Elisa
AU  - Patel,Kashyap A.
AU  - Ellard,Sian
AU  - Morgan,Noel G.
AU  - Cheesman,Edmund
AU  - Banerjee,Indraneel
AU  - Hattersley,Andrew T.
AU  - Dunne,Mark J.
AU  - Richardson,Sarah J.
AU  - Flanagan,Sarah E.
TI  - Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism
PY  - 2022///-11
KW  - Text
KW  - local
N1  - /pmc/articles/PMC7614032; /pubmed/36333503
N2  - Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function(1). This silencing is largely controlled by non-coding elements and their disruption might cause human disease(2). We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1). HK1 is widely expressed across all tissues except for liver and pancreatic beta-cells and is thus termed a "disallowed gene" in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta-cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene
UR  - http://dx.doi.org/10.1038/s41588-022-01204-x
ER  -